Pharmacologically-induced perturbations in striatal dopaminergic transmission lead to compensatory, homeostatic adaptations in the firing rate and the neurotransmitter dynamics of the nigro-striatal dopaminergic pathway. The biochemical responses appear to be mediated through alterations in the kinetic properties of the rate-limiting enzyme in dopamine (DA) biosynthesis, tyrosine hydroxylase (TOH). Haloperidol and amphetamine administration yield opposite adaptive changes in the physiology of this pathway, and thus provide a model system in which the regulatory inputs mediating compensatory changes in nerve ending DA dynamics and the kinetic state of TOH may be assessed. The state of nerve ending DA biosynthesis may be specified by contributions from neurotransmitter receptors (ACh, DA, GABA, 5HT) on the DA cell body, the level of nerve impulse flow in the DA neuron, and the content of multiple pools of DA and the degree of occupancy of neurotransmitter receptors at the nerve ending. The relative contribution of regulatory inputs in specifying the state of DA dynamics will be assessed by combining systemic drug administration with unilateral microinjections of specific agents into the pars compacta of the substantia nigra or the striatum. By specifically manipulating one or more potential regulatory inputs as a function of haloperidol and amphetamine administration, the role of these inputs in triggering, mediating, and/or maintaining compensatory adaptation may be defined. Measurements of in vivo DA synthesis, levels, and turnover, as well as in vitro synaptosomal DA biosynthesis and the kinetic state of TOH will provide an accurate index of alterations in striatal nerve ending dynamics. Concomitant with biochemical determinations after unilateral intracerebral injections, rotational behavior in animals will be assessed both as an index of striatal DA function, and to delineate the role of intranigral non-dopaminergic transmitters in rotational behavior.